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General Information About Salivary Gland Cancer

Incidence and Mortality

Salivary gland tumors are a morphologically and clinically diverse group of neoplasms, which may present significant diagnostic and management challenges. These tumors are rare, with an overall incidence in the Western world of approximately 2.5 cases to 3.0 cases per 100,000 per year.[1] Malignant salivary gland neoplasms account for more than 0.5% of all malignancies and approximately 3% to 5% of all head and neck cancers.[1,2] Most patients with malignant salivary gland tumors are in the sixth or seventh decade of life.[3,4]

Carcinogenesis and Risk Factors

Although exposure to ionizing radiation has been implicated as a cause of salivary gland cancer, the etiology of most salivary gland cancers cannot be determined.[2,3,5,6] Occupations associated with an increased risk for salivary gland cancers include rubber products manufacturing, asbestos mining, plumbing, and some types of woodworking.[3]

Anatomy

Tumors of the salivary glands comprise those in the major glands (e.g., parotid, submandibular, and sublingual) and the minor glands (e.g., oral mucosa, palate, uvula, floor of mouth, posterior tongue, retromolar area and peritonsillar area, pharynx, larynx, and paranasal sinuses).[2,7] Minor salivary gland lesions are most frequently seen in the oral cavity.[2]

Of salivary gland neoplasms, more than 50% are benign, and approximately 70% to 80% of all salivary gland neoplasms originate in the parotid gland.[1,2,8] The palate is the most common site of minor salivary gland tumors. The frequency of malignant lesions varies by site. Approximately 20% to 25% of parotid tumors, 35% to 40% of submandibular tumors, 50% of palate tumors, and more than 90% of sublingual gland tumors are malignant.[1,9]

Histopathology

Histologically, salivary gland tumors represent the most heterogenous group of tumors of any tissue in the body.[10] Although almost 40 histologic types of epithelial tumors of the salivary glands exist, some are exceedingly rare and may be the subject of only a few case reports.[1,11] The most common benign major and minor salivary gland tumor is the pleomorphic adenoma, which comprises about 50% of all salivary gland tumors and 65% of parotid gland tumors.[1] The most common malignant major and minor salivary gland tumor is the mucoepidermoid carcinoma, which comprises about 10% of all salivary gland neoplasms and approximately 35% of malignant salivary gland neoplasms.[1,12] This neoplasm occurs most often in the parotid gland.[2,12,13] This type and other histologic types of salivary gland neoplasms are reviewed in detail in the Cellular Classification of Salivary Gland Treatment section of this summary.

Clinical Presentation

Most patients with benign tumors of the major or minor salivary glands present with painless swelling of the parotid, submandibular, or the sublingual glands. Neurological signs, such as numbness or weakness caused by nerve involvement, typically indicate a malignancy.[2] Facial nerve weakness that is associated with a parotid or submandibular tumor is an ominous sign. Persistent facial pain is highly suggestive of malignancy; approximately 10% to 15% of malignant parotid neoplasms present with pain.[8,14] (Refer to the PDQ summary on Pain for more information.) The majority of parotid tumors, both benign and malignant, however, present as an asymptomatic mass in the gland.[2,8]

Prognostic Factors

Early-stage low-grade malignant salivary gland tumors are usually curable by adequate surgical resection alone. The prognosis is more favorable when the tumor is in a major salivary gland; the parotid gland is most favorable, then the submandibular gland; the least favorable primary sites are the sublingual and minor salivary glands. Large bulky tumors or high-grade tumors carry a poorer prognosis and may best be treated by surgical resection combined with postoperative radiation therapy.[15] The prognosis also depends on the following:[16,17]

Gland in which they arise.

Histology.

Grade (i.e., degree of malignancy).

Extent of primary tumor (i.e., the stage).

Whether the tumor involves the facial nerve, has fixation to the skin or deep structures, or has spread to lymph nodes or distant sites.

Follow-up and Survivorship

Overall, clinical stage, particularly tumor size, may be the crucial factor to determine the outcome of salivary gland cancer and may be more important than histologic grade.[18]

Treatment management

Perineural invasion can also occur, particularly in high-grade adenoid cystic carcinoma, and should be specifically identified and treated.[19] Radiation therapy may increase the chance of local control and increase the survival of patients when adequate margins cannot be achieved.[20][Level of evidence: 3iiiDii] Unresectable or recurrent tumors may respond to chemotherapy.[21,22,23] Fast neutron-beam radiation therapy or accelerated hyperfractionated photon-beam schedules have been shown to be effective in the treatment of inoperable, unresectable, and recurrent tumors.[24,25,26]

Follow-up after treatment

Complications of surgical treatment for parotid neoplasms include facial nerve dysfunction and Frey syndrome also known as gustatory flushing and sweating and the auriculotemporal syndrome.[8] Frey syndrome has been successfully treated with injections of botulinum toxin A.[27,28,29]

Cellular Classification of Salivary Gland Cancer

Salivary gland neoplasms are remarkable for their histologic diversity. These neoplasms include benign and malignant tumors of epithelial, mesenchymal, and lymphoid origin. Salivary gland tumors pose a particular challenge to the surgical pathologist. Differentiating benign from malignant tumors may be difficult, primarily because of the complexity of the classification and the rarity of several entities, which may exhibit a broad spectrum of morphologic diversity in individual lesions.[1] In some cases, hybrid lesions may be seen.[2] The key guiding principle to establish the malignant nature of a salivary gland tumor is the demonstration of an infiltrative margin.[1]

The following cellular classification scheme draws heavily from a scheme published by the Armed Forces Institute of Pathology (AFIP).[3] Malignant nonepithelial neoplasms are included in the scheme because these neoplasms comprise a significant proportion of salivary gland neoplasms seen in the clinical setting. For completeness, malignant secondary tumors are also included in the scheme.

Where AFIP statistics regarding the incidence, or relative frequency, of particular histopathologies are cited, some bias may exist because of the AFIP methods of case accrual as a pathology reference service. When possible, other sources are cited for incidence data. Notwithstanding the AFIP data, the incidence of a particular histopathology has been found to vary considerably depending upon the study cited. This variability in reporting may be partially caused by the rare incidence of many salivary gland neoplasms.

Epithelial Neoplasms

The clinician should be aware that several benign epithelial salivary gland neoplasms have malignant counterparts, which are shown below:[3]

Histologic grading of salivary gland carcinomas is important to determine the proper treatment approach, though it is not an independent indicator of the clinical course and must be considered in the context of the clinical stage. Clinical stage, particularly tumor size, may be the critical factor to determine the outcome of salivary gland cancer and may be more important than histologic grade.[1] For example, stage I intermediate-grade or high-grade mucoepidermoid carcinomas can be successfully treated, whereas low-grade mucoepidermoid carcinomas that present as stage III disease may have a very aggressive clinical course.[4]

Grading is used primarily for mucoepidermoid carcinomas, adenocarcinomas, not otherwise specified (NOS), adenoid cystic carcinomas, and squamous cell carcinomas.[1,3] Various other salivary gland carcinomas can also be categorized according to histologic grade as follows:[3,5,6,7,8]

Low grade

Acinic cell carcinoma.

Basal cell adenocarcinoma.

Clear cell carcinoma.

Cystadenocarcinoma.

Epithelial-myoepithelial carcinoma.

Mucinous adenocarcinoma.

Polymorphous low-grade adenocarcinoma (PLGA).

Low grade, intermediate grade, and high grade

Adenocarcinoma, NOS.

Mucoepidermoid carcinoma.*

Squamous cell carcinoma.

Intermediate grade and high grade

Myoepithelial carcinoma.

High grade

Anaplastic small cell carcinoma.

Carcinosarcoma.

Large cell undifferentiated carcinoma.

Small cell undifferentiated carcinoma.

Salivary duct carcinoma.

*Some investigators consider mucoepidermoid carcinoma to be of only two grades: low grade and high grade.[5]

Salivary gland carcinomas and mixed tumors

Mucoepidermoid carcinoma.

Adenoid cystic carcinoma.

Adenocarcinomas.

Acinic cell carcinoma.

PLGA.

Adenocarcinoma, NOS.

Rare adenocarcinomas.

Basal cell adenocarcinoma.

Clear cell carcinoma.

Cystadenocarcinoma.

Sebaceous adenocarcinoma.

Sebaceous lymphadenocarcinoma.

Oncocytic carcinoma.

Salivary duct carcinoma.

Mucinous adenocarcinoma.

Malignant mixed tumors.

Carcinoma ex pleomorphic adenoma.

Carcinosarcoma.

Metastasizing mixed tumor.

Rare carcinomas.

Primary squamous cell carcinoma.

Epithelial-myoepithelial carcinoma.

Anaplastic small cell carcinoma.

Undifferentiated carcinomas.

Small cell undifferentiated carcinoma.

Large cell undifferentiated carcinoma.

Lymphoepithelial carcinoma.

Myoepithelial carcinoma.

Adenosquamous carcinoma.

Mucoepidermoid carcinoma

Mucoepidermoid carcinoma is a malignant epithelial tumor that is composed of various proportions of mucous, epidermoid (e.g., squamous), intermediate, columnar, and clear cells and often demonstrates prominent cystic growth. It is the most common malignant neoplasm observed in the major and minor salivary glands.[1,9] Mucoepidermoid carcinoma represents 29% to 34% of malignant tumors originating in both major and minor salivary glands.[3,5,10,11] In two large retrospective series, 84% to 93% of cases originated in the parotid gland.[12,13] With regard to malignant tumors of the minor salivary glands, mucoepidermoid carcinoma shows a strong predilection for the lower lip.[3,14] In an AFIP review of civilian cases, the mean age of patients was 47 years, with an age range of 8 years to 92 years.[3] Prior exposure to ionizing radiation appears to substantially increase the risk of developing malignant neoplasms of the major salivary glands, particularly mucoepidermoid carcinoma.[3,13]

Most patients are asymptomatic and present with solitary, painless masses. Symptoms include pain, drainage from the ipsilateral ear, dysphagia, trismus, and facial paralysis.[3] (Refer to the PDQ summary on Pain for more information.)

Microscopic grading of mucoepidermoid carcinoma is important to determine the prognosis.[1,12,15] Mucoepidermoid carcinomas are graded as low grade, intermediate grade, and high grade. Grading parameters with point values include the following:

Intracystic component (+2).

Neural invasion present (+2).

Necrosis present (+3).

Mitosis (≥4 per 10 high-power field [+3]).

Anaplasia present (+4).

Total point scores are 0 to 4 for low grade, 5 to 6 for intermediate grade, and 7 to 14 for high grade.

In a retrospective review of 243 cases of mucoepidermoid carcinoma of the major salivary glands, a statistically significant correlation was shown between this point-based grading system and outcome for parotid tumors but not for submandibular tumors.[12] Another retrospective study that used this histologic grading system indicated that tumor grade correlated well with prognosis for mucoepidermoid carcinoma of the major salivary glands, excluding submandibular tumors, and minor salivary glands.[13] A modification of this grading system placed more emphasis on features of tumor invasion.[16] Nonetheless, though tumor grade may be useful, stage appears to be a better indicator of prognosis.[3,16]

Cytogenetically, mucoepidermoid carcinoma is characterized by a t(11;19)(q14–21;p12–13) translocation, which is occasionally the sole cytogenetic alteration.[17,18,19] This translocation creates a novel fusion product, MECT1-MAML2, which disrupts a Notch signaling pathway.[20] Notch signaling plays a key role in the normal development of many tissues and cell types, through diverse effects on cellular differentiation, survival, and/or proliferation, and may be involved in a wide variety of human neoplasms.[21]

Rarely, mucoepidermoid carcinoma may originate within the jaws. This tumor type is known as central mucoepidermoid carcinoma.[3] The mandibular to maxillary predilection is approximately 3:1.[22]

Adenoid cystic carcinoma

Adenoid cystic carcinoma, formerly known as cylindroma, is a slow growing but aggressive neoplasm with a remarkable capacity for recurrence.[23] Morphologically, three growth patterns have been described: cribriform, or classic pattern; tubular; and solid, or basaloid pattern. The tumors are categorized according to the predominant pattern.[3,23,24,25] The cribriform pattern shows epithelial cell nests that form cylindrical patterns. The lumina of these spaces contain periodic acid-Schiff (PAS)-positive mucopolysaccharide secretions. The tubular pattern reveals tubular structures that are lined by stratified cuboidal epithelium. The solid pattern shows solid groups of cuboidal cells. The cribriform pattern is the most common, and the solid pattern is the least common.[26] Solid adenoid cystic carcinoma is a high-grade lesion with reported recurrence rates of as much as 100% compared with 50% to 80% for the tubular and cribriform variants.[25]

In a review of its case files, the AFIP found adenoid cystic carcinoma to be the fifth most common malignant epithelial tumor of the salivary glands after mucoepidermoid carcinomas; adenocarcinomas, NOS; acinic cell carcinomas; and PLGA.[3] Other series, however, report adenoid cystic carcinoma to be the second most common malignant tumor with an incidence or relative frequency of approximately 20%.[1] In the AFIP data, this neoplasm constitutes approximately 7.5% of all epithelial malignancies and 4% of all benign and malignant epithelial salivary gland tumors. The peak incidence for this tumor is reported to be in the fourth through sixth decades of life.[3]

This neoplasm typically develops as a slow growing swelling in the preauricular or submandibular region. Pain and facial paralysis develop frequently during the course of the disease and are likely related to the associated high incidence of nerve invasion.[3] (Refer to the PDQ summary on Pain for more information.) Regardless of histologic grade, adenoid cystic carcinomas, with their unusually slow biologic growth, tend to have a protracted course and ultimately a poor outcome, with a 10-year survival reported to be less than 50% for all grades.[1,27] These carcinomas typically show frequent recurrences and late distant metastases.[1,28] Clinical stage may be a better prognostic indicator than histologic grade.[28,29] In a retrospective review of 92 cases, a tumor size larger than 4 cm was associated with an unfavorable clinical course in all cases.[30]

Adenocarcinomas

Acinic cell carcinoma

Acinic cell carcinoma, also known as acinic cell adenocarcinoma, is a malignant epithelial neoplasm in which the neoplastic cells express acinar differentiation. By conventional use, the term acinic cell carcinoma is defined by cytologic differentiation towards serous acinar cells, as opposed to mucous acinar cells, whose characteristic feature is cytoplasmic periodic acid-Schiff (PAS)-positive zymogen-type secretory granules.[3] In AFIP data of salivary gland neoplasms, acinic cell carcinoma is the third most common salivary gland epithelial neoplasm after mucoepidermoid carcinoma and adenocarcinoma, NOS.[3] In these data, acinic cell carcinoma comprised 17% of primary malignant salivary gland tumors or about 6% of all salivary gland neoplasms; more than 80% occur in the parotid gland; women were affected more than men; and the mean age was 44 years. Other studies have reported a relative frequency of acinic cell carcinoma from 0% to 19% of malignant salivary gland neoplasms.[3]

Clinically, patients typically present with a slowly enlarging mass in the parotid region. Pain is a symptom in more than 33% of patients. (Refer to the PDQ summary on Pain for more information.) For acinic cell carcinoma, staging is likely a better predictor of outcome than histologic grading.[3] In a retrospective review of 90 cases, poor prognostic features included pain or fixation; gross invasion; and microscopic features of desmoplasia, atypia, or increased mitotic activity. Neither morphologic pattern nor cell composition was a predictive feature.[31]

PLGA

PLGA is a malignant epithelial tumor that is essentially limited to occurrence in minor salivary gland sites and is characterized by bland, uniform nuclear features; diverse but characteristic architecture; infiltrative growth; and perineural infiltration.[3] In a series of 426 minor salivary gland tumors, PLGA represented 11% of all tumors and 26% of those that were malignant.[32] In minor gland sites, PLGA is twice as frequent as adenoid cystic carcinoma, and among all benign and malignant salivary gland neoplasms, only pleomorphic adenoma and mucoepidermoid carcinoma are more common.[3] In the AFIP case files, more than 60% of tumors occurred in the mucosa of either the soft or hard palates, approximately 16% occurred in the buccal mucosa, and 12% occurred in the upper lip. The average age of patients is reported to be 59 years, with 70% of patients between the ages of 50 and 79 years.[3] The female to male ratio is about 2:1, a proportion greater than for malignant salivary gland tumors in general.[3,33]

PLGA typically presents as a firm, nontender swelling involving the mucosa of the hard and soft palates (i.e., it is often found at their junction), the cheek, or the upper lip. Discomfort, bleeding, telangiectasia, or ulceration of the overlying mucosa may occasionally occur.[3] This salivary gland neoplasm typically runs a moderately indolent course. In a study of 40 cases with long-term follow-up, overall survival was 80% at 25 years.[34] Because of the unpredictable behavior of the tumor, some investigators consider the qualifying term, low grade, to be misleading and instead prefer the term, polymorphous adenocarcinoma.[1]

Adenocarcinoma, NOS

Adenocarcinoma, NOS, is a salivary gland carcinoma that shows glandular or ductal differentiation but lacks the prominence of any of the morphologic features that characterize the other, more specific carcinoma types. The diagnosis of adenocarcinoma, NOS, is essentially one of exclusion. In an AFIP review of cases, adenocarcinoma, NOS, was second only to mucoepidermoid carcinoma in frequency among malignant salivary gland neoplasms.[3] Other series have reported an incidence of 4% to 10%.[1] In AFIP files, the mean patient age was 58 years.[3] Approximately 40% and 60% of tumors occurred in the major and minor salivary glands, respectively. Among the major salivary gland tumors, 90% occurred in the parotid gland. Adenocarcinoma, NOS is graded in a similar way to extrasalivary lesions according to the degree of differentiation.[1] Tumor grades include low grade, intermediate grade, and high-grade categories.[3]

Patients with tumors in the major salivary glands typically present with solitary, painless masses.[35] Two retrospective studies indicate that survival is better for patients with tumors of the oral cavity than for those with tumors of the parotid and submandibular glands.[35,36] These studies differ regarding the prognostic significance of tumor grade.

Rare adenocarcinomas

Basal cell adenocarcinoma

Basal cell adenocarcinoma, also known as basaloid salivary carcinoma, carcinoma ex monomorphic adenoma, malignant basal cell adenoma, malignant basal cell tumor, and basal cell carcinoma, is an epithelial neoplasm that is cytologically similar to basal cell adenoma but is infiltrative and has a small potential for metastasis.[3] In AFIP case files spanning almost 11 years, basal cell carcinoma comprised 1.6% of all salivary gland neoplasms and 2.9% of salivary gland malignancies.[3] Nearly 90% of tumors occurred in the parotid gland.[3,37] The average age of patients is reported to be 60 years.[3]

Similar to most salivary gland neoplasms, swelling is typically the only sign or symptom experienced.[37] A sudden increase in size may occur in a few patients.[38] Basal cell carcinomas are low-grade carcinomas that are infiltrative, locally destructive, and tend to recur. The carcinomas occasionally metastasize. In a retrospective series that included 29 patients, there were recurrences in 7 patients and metastases in 3 patients.[37] In another retrospective review that included 72 patients, 37% of the patients experienced local recurrences.[38] The overall prognosis for patients with this tumor is good.[37,38]

Clear cell carcinoma

Clear cell carcinoma, also known as clear cell adenocarcinoma, is a very rare malignant epithelial neoplasm composed of a monomorphous population of cells that have optically clear cytoplasm with standard hematoxylin and eosin stains and lack features of other specific neoplasms. Because of inconsistencies in the methods of reporting salivary gland neoplasms, meaningful incidence rates for this tumor are difficult to derive from the literature.[3] Most cases involve the minor salivary glands.[1,3,39,40,41] In the AFIP case files, the mean age of patients is approximately 58 years.[3]

In most patients, swelling is the only symptom. Clear cell adenocarcinoma is a low-grade neoplasm. As of 1996, the AFIP reported that no patient is known to have died as a result of this tumor.[3]

Cystadenocarcinoma

Cystadenocarcinoma, also known as malignant papillary cystadenoma, mucus-producing adenopapillary, or nonepidermoid, carcinoma; low-grade papillary adenocarcinoma of the palate; and papillary adenocarcinoma, is a rare malignant epithelial tumor characterized histologically by prominent cystic and, frequently, papillary growth but lacking features that characterize cystic variants of several more common salivary gland neoplasms. Cystadenocarcinoma is the malignant counterpart of cystadenoma.[3]

In a review that included 57 patients, the AFIP found that men and women are affected equally; the average patient age was approximately 59 years; and approximately 65% of the tumors occurred in the major salivary glands, and primarily in the parotid.[3] Most patients present with a slowly growing asymptomatic mass. Clinically, this neoplasm is rarely associated with pain or facial paralysis. Cystadenocarcinoma is considered to be a low-grade neoplasm.[3]

Sebaceous adenocarcinoma

Sebaceous adenocarcinoma is a rare malignant epithelial tumor composed of islands and sheets of cells that have morphologically atypical nuclei, an infiltrative growth pattern, and focal sebaceous differentiation. This is a very rare tumor, as few cases have been reported in the literature.[3] Almost all cases occur in the parotid gland.[3] The average age of patients is reported to be 69 years.[42]

An equal number of patients present with a painless, slow-growing, asymptomatic swelling or pain. A few experience facial paralysis.[3] Most sebaceous adenocarcinomas are probably intermediate-grade malignancies. Tumor recurs in about 33% of cases.[43,44]

Sebaceous lymphadenocarcinoma

Sebaceous lymphadenocarcinoma is an extremely rare malignant tumor that represents carcinomatous transformation of sebaceous lymphadenoma. The carcinoma element may be sebaceous adenocarcinoma or some other specific or nonspecific form of salivary gland cancer.[3] Only three cases have been reported in the literature.[43,45] The three cases occurred in or around the parotid gland. All patients were in their seventh decade of life. Two of the three patients were asymptomatic. One had tenderness on palpation. Case reports suggest that this is a low-grade malignancy with a good prognosis.[44,45]

Oncocytic carcinoma

Oncocytic carcinoma, also known as oncocytic adenocarcinoma, is a rare, predominantly oncocytic neoplasm whose malignant nature is reflected both by its abnormal morphologic features and infiltrative growth. Oncocytic carcinoma represents less than 1% of almost 3,100 salivary gland tumors accessioned to the AFIP files during a 10-year period.[3] Most cases occur in the parotid gland. The average age of patients in the AFIP series was 63 years.[3]

Approximately 33% of the patients usually develop parotid masses that cause pain or paralysis.[46] Oncocytic carcinoma is a high-grade carcinoma. Tumors smaller than 2 cm have a better prognosis than larger tumors.[6]

Salivary duct carcinoma

Salivary duct carcinoma, also known as salivary duct adenocarcinoma, is a rare, typically high-grade malignant epithelial neoplasm composed of structures that resemble expanded salivary gland ducts. A low-grade variant exists.[47] Incidence rates vary depending upon the study cited.[3] In the AFIP files, salivary duct carcinomas represent only 0.2% of all epithelial salivary gland neoplasms. More than 85% of cases involve the parotid gland and approximately 75% of patients are men. The peak incidence is reported to be in the seventh and eighth decades of life.[3]

Clinically, parotid swelling is the most common sign. Facial nerve dysfunction or paralysis occur in more than 25% of patients and may be the initial manifestation.[3] The high-grade variant of this neoplasm is one of the most aggressive types of salivary gland carcinoma and is typified by local invasion, lymphatic and hematogenous spread, and poor prognosis.[3,7] In a retrospective review of 104 cases, 33% of patients developed local recurrence, and 46% of patients developed distant metastasis.[48]

Mucinous adenocarcinoma

Mucinous adenocarcinoma is a rare malignant neoplasm characterized by large amounts of extracellular epithelial mucin that contains cords, nests, and solitary epithelial cells. The incidence is unknown. Limited data indicate that most, if not all, occur in the major salivary glands with the submandibular gland as the predominant site.[3,49] These tumors may be associated with dull pain and tenderness.[3,49] This neoplasm may be considered to be low grade.[3]

Carcinoma ex pleomorphic adenoma, also known as carcinoma ex mixed tumor, is a carcinoma that shows histologic evidence of arising from or in a benign pleomorphic adenoma.[50] Diagnosis requires the identification of benign tumor in the tissue sample.[51] The incidence or relative frequency of this tumor varies considerably depending on the study cited.[1] A review of material at the AFIP showed carcinoma ex pleomorphic adenoma to comprise 8.8% of all mixed tumors and 4.6% of all malignant salivary gland tumors, ranking it as the sixth most common malignant salivary gland tumor after mucoepidermoid carcinoma; adenocarcinoma, NOS; acinic cell carcinoma; polymorphous low-grade adenocarcinoma; and adenoid cystic carcinoma.[3] The neoplasm occurs primarily in the major salivary glands.[52]

The most common clinical presentation is a painless mass.[3] Approximately 33% of patients may experience facial paralysis.[53] Depending on the series cited, survival times vary significantly: 25% to 65% at 5 years, 24% to 50% at 10 years, 10% to 35% at 15 years, and 0% to 38% at 20 years.[3] In addition to tumor stage, histologic grade and degree of invasion are important parameters to determine prognosis.[54]

Carcinosarcoma

Carcinosarcoma, also known as true malignant mixed tumor, is a rare malignant salivary gland neoplasm that contains both carcinoma and sarcoma components. Either or both components are expressed in metastatic foci. Some carcinosarcomas develop de novo while others develop in association with benign mixed tumor. This neoplasm is rare; only eight cases exist in the AFIP case files.[3] At one facility, only 11 cases were recorded over a 32-year period.[8] The majority of tumors occur in the major salivary glands.

Swelling, pain, nerve palsy, and ulceration have been frequent clinical findings. Carcinosarcoma is an aggressive, high-grade malignancy. In the largest series reported, which consisted of 12 cases, the average survival period was 3.6 years.[8]

Metastasizing mixed tumor

Metastasizing mixed tumor is a very rare histologically benign salivary gland neoplasm that inexplicably metastasizes. Often a long interval occurs between the diagnosis of the primary tumor and the metastases. The histologic features are within the spectrum of features that typify pleomorphic adenoma.[3] The majority occur in the major salivary glands. The primary neoplasm is typically a single, well-defined mass. Recurrences, which may be multiple, have been reported to occur for as many as 26 years after excision of the primary neoplasm.[55]

Rare carcinomas

Primary squamous cell carcinoma

Primary squamous cell carcinoma, also known as primary epidermoid carcinoma, is a malignant epithelial neoplasm of the major salivary glands that is composed of squamous (i.e., epidermoid) cells. Diagnosis requires the exclusion of primary disease located in some other head and neck site; indeed, most squamous cell carcinomas of the major salivary glands represent metastatic disease.[3] This diagnosis is not made in minor salivary glands because distinction from the more common mucosal squamous cell carcinoma is not possible.[3] Previous exposure to ionizing radiation appears to increase the risk for developing this neoplasm.[11,56,57] The median time between radiation therapy and diagnosis of the neoplasm is approximately 15.5 years.[11] The reported frequency of this tumor among all major salivary gland tumors has varied from 0.9% to 4.7%.[3,10] In AFIP major salivary gland accessions from 1985 to 1996, primary squamous cell carcinoma comprised 2.7% of all tumors; 5.4% of malignant tumors; and 2.5% and 2.8%, respectively, of all parotid and submandibular tumors.[3] The average age in the AFIP registry was 64 years.[3] This neoplasm occurs in the parotid gland almost nine times more often than in the submandibular gland.[3,57] There is a strong male predilection.[3,11,57,58,59] This tumor is graded in a similar way to extrasalivary lesions according to the degree of differentiation, namely, low grade, intermediate grade, and high grade.[1]

Most patients present with an asymptomatic mass in the parotid region. Other symptoms may include a painful mass and facial nerve palsy.[57] The prognosis for this neoplasm is poor. In a 30-year retrospective analysis of 50 cases of squamous cell carcinoma of the salivary glands, survival rates at 5 years and 10 years were 24% and 18%, respectively.[57]

Epithelial-myoepithelial carcinoma

Epithelial-myoepithelial carcinoma, also known as adenomyoepithelioma, clear cell adenoma, tubular solid adenoma, monomorphic clear cell tumor, glycogen-rich adenoma, glycogen-rich adenocarcinoma, clear cell carcinoma, and salivary duct carcinoma, is an uncommon, low-grade epithelial neoplasm composed of variable proportions of ductal and large, clear-staining, differentiated myoepithelial cells. The tumor comprises approximately 1% of all epithelial salivary gland neoplasms.[3,60] It is predominantly a tumor of the parotid gland. In the AFIP case files, the mean age of patients is about 60 years and about 60% of the patients are female.[3]

Localized swelling is commonly the only symptom, but occasionally patients experience facial weakness or pain.[61,62] Overall, epithelial-myoepithelial carcinoma is a low-grade carcinoma that recurs frequently, has a tendency to metastasize to periparotid and cervical lymph nodes, and occasionally results in distant metastasis and death.[60,62,63,64]

Anaplastic small cell carcinoma

Anaplastic small cell carcinoma of the salivary glands was first described in 1972.[65] Subsequent histochemical and electron microscopic studies have supported the neuroendocrine nature of this tumor.[66,67] Microscopically, the tumor cells have oval, hyperchromatic nuclei and scant amount of cytoplasm and are organized in sheets, strands, and nests. The mitotic rate is high. Neuroendocrine carcinomas are more frequently found in the minor salivary glands and have a better survival rate compared with small cell carcinomas of the lung.[68] The undifferentiated counterpart of this neoplasm is the small cell undifferentiated carcinoma.

Undifferentiated carcinomas

Undifferentiated carcinomas of salivary glands are a group of uncommon malignant epithelial neoplasms that lack the specific light-microscopic morphologic features of other types of salivary gland carcinomas. These carcinomas are histologically similar to undifferentiated carcinomas that arise in other organs and tissues. Accordingly, metastatic carcinoma is a primary concern in the differential diagnosis of these neoplasms.[3]

Small cell undifferentiated carcinoma

Small cell undifferentiated carcinoma, also known as extrapulmonary oat cell carcinoma, is a rare, primary malignant tumor that, with conventional light microscopy, is composed of undifferentiated cells and, with ultrastructural or immunohistochemical studies, does not demonstrate neuroendocrine differentiation. This is the undifferentiated counterpart of anaplastic small cell carcinoma (Refer to the anaplastic small cell carcinoma section of this summary.)

In an AFIP review of case files, small cell carcinoma represented 1.8% of all major salivary gland malignancies; the mean age of patients was 56 years.[3] In 50% of the cases, patients present with an asymptomatic parotid mass of 3 months' or less duration.[68,69,70] This is a high-grade neoplasm. In a retrospective review of 12 cases, a tumor size of more than 4 cm was found to be the most important predictor of behavior. In another small retrospective series, estimated survival rates at 2 and 5 years were 70% and 46%, respectively.[68]

Large cell undifferentiated carcinoma

Large cell undifferentiated carcinoma is a tumor in which features of acinar, ductal, epidermoid, or myoepithelial differentiation are absent under light microscopy, though occasionally, poorly formed duct–like structures are found. This neoplasm accounts for approximately 1% of all epithelial salivary gland neoplasms.[3,53,71,72] Most of these tumors occur in the parotid gland.[70,72] In AFIP data, the peak incidence is in the seventh to eighth decades of life.[3]

Rapid growth of a parotid swelling is a common clinical presentation.[59] This is a high-grade neoplasm that frequently metastasizes and has a poor prognosis. Neoplasms 4 cm or larger may have a particularly poor outcome.[70,72]

Lymphoepithelial carcinoma

Lymphoepithelial carcinoma, also known as undifferentiated carcinoma with lymphoid stroma and carcinoma ex lymphoepithelial lesion, is an undifferentiated tumor that is associated with a dense lymphoid stroma. An exceptionally high incidence of this tumor is found in the Eskimo and Inuit populations.[3,73] This neoplasm has been associated with Epstein-Barr virus infection.[74,75] Of the occurrences, 80% are in the parotid gland.[3]

In addition to the presence of a parotid or submandibular mass, pain is a frequent symptom, and facial nerve palsy occurs in as many as 20% of patients.[76] (Refer to the PDQ summary on Pain for more information.) Of the patients, more than 40% have metastases to cervical lymph nodes at initial presentation, 20% develop local recurrences or lymph node metastases, and 20% develop distant metastases within 3 years following therapy.[73,76,77,78]

Myoepithelial carcinoma

Myoepithelioma carcinoma is a rare, malignant salivary gland neoplasm in which the tumor cells almost exclusively manifest myoepithelial differentiation. This neoplasm represents the malignant counterpart of benign myoepithelioma.[3] To date, the largest series reported involves 25 cases.[79] Approximately 66% of the tumors occur in the parotid gland.[3,74] The mean age of patients is reported to be 55 years.[79]

The majority of patients present with the primary complaint of a painless mass.[79] This is an intermediate grade to high-grade carcinoma.[3,79] Histologic grade does not appear to correlate well with clinical behavior; tumors with a low-grade histologic appearance may behave aggressively.[79]

Adenosquamous carcinoma

Adenosquamous carcinoma is an extremely rare malignant neoplasm that simultaneously arises from surface mucosal epithelium and salivary gland ductal epithelium. The carcinoma shows histopathologic features of both squamous cell carcinoma and adenocarcinoma. Only a handful of reports have discussed this tumor.[3]

In addition to swelling, adenosquamous carcinoma produces visible changes in the mucosa including erythema, ulceration, and induration. Pain frequently accompanies ulceration. Limited data indicate that this is a highly aggressive neoplasm with a poor prognosis.[3]

Nonepithelial Neoplasms

Lymphomas and benign lymphoepithelial lesion

Lymphomas of the major salivary glands are characteristically of the non-Hodgkin type. In an AFIP review of case files, non-Hodgkin lymphoma accounted for 16.3% of all malignant tumors that occurred in the major salivary glands; disease in the parotid gland accounted for about 80% of all cases.[3]

Patients with benign lymphoepithelial lesion (e.g., Mikulicz disease), which is a manifestation of the autoimmune disease, Sjögren syndrome, are at an increased risk for development of non-Hodgkin lymphoma.[80,81,82,83,84] Benign lymphoepithelial lesion is clinically characterized by diffuse and bilateral enlargement of the salivary and lacrimal glands.[23] Morphologically, a salivary gland lesion is composed of prominent myoepithelial islands surrounded by a lymphocytic infiltrate. Germinal centers are often present in the lymphocytic infiltrate.[23] Immunophenotypically and genotypically, the lymphocytic infiltrate is composed of B-lymphocytes and T-lymphocytes, which are polyclonal. In some instances, the B-cell lymphocytic infiltrate can undergo clonal expansion and evolve into frank non-Hodgkin lymphoma. The vast majority of the non-Hodgkin lymphomas arising in a background of benign lymphoepithelial lesions are marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT).[81,82,83,84] MALT lymphomas of the salivary glands, like their counterparts in other anatomic sites, typically display relatively indolent clinical behavior.[3,85]

Primary non-MALT lymphomas of the salivary glands may also occur and appear to have a prognosis similar to those in patients who have histologically identical nodal lymphomas.[86,87] Unlike non-Hodgkin lymphoma, involvement of the major salivary glands by Hodgkin lymphoma is rare. Most tumors occur in the parotid gland.[3] The most common histologic types encountered are the nodular sclerosing and lymphocyte-predominant variants.[88,89]

Mesenchymal neoplasms

Mesenchymal neoplasms account for 1.9% to 5% of all neoplasms that occur within the major salivary glands.[90,91] These cellular classifications pertain to major salivary gland tumors. Because the minor salivary glands are small and embedded within fibrous connective tissue, fat, and skeletal muscle, the origin of a mesenchymal neoplasm from stroma cannot be determined.[3] The types of benign mesenchymal salivary gland neoplasms include hemangiomas, lipomas, and lymphangiomas.

Malignant mesenchymal salivary gland neoplasms include malignant schwannomas, hemangiopericytomas, malignant fibrous histiocytomas, rhabdomyosarcomas, and fibrosarcomas, among others; in the major salivary glands, these neoplasms represent approximately 0.5% of all benign and malignant salivary gland tumors and approximately 1.5% of all malignant tumors.[90,92,93] Of importance is to establish a primary salivary gland origin for these tumors by excluding the possibilities of metastasis and direct extension from other sites. In addition, the diagnosis of salivary gland carcinosarcoma should be excluded.[3] Primary salivary gland sarcomas behave like their soft tissue counterparts in which prognosis is related to sarcoma type, histologic grade, tumor size, and stage.[93,94] (Refer to the PDQ summary on Adult Soft Tissue Sarcoma Treatment for more information.) A comprehensive review of salivary gland mesenchymal neoplasms can be found elsewhere.[95]

Direct invasion from cancers that lie adjacent to the salivary glands.

Hematogenous metastases from distant primary tumors.

Lymphatic metastases to lymph nodes within the salivary gland.

Direct invasion of nonsalivary gland tumors into the major salivary glands is principally from squamous cell and basal cell carcinomas of the overlying skin.

Approximately 80% of metastases to the major salivary glands may be from primary tumors elsewhere in the head and neck; the remaining 20% may be from infraclavicular sites.[96,97] The parotid gland is the site of 80% to 90% of the metastases, and the remainder involve the submandibular gland.[97,98] In a decade-long AFIP experience, metastatic tumors constituted approximately 10% of malignant neoplasms in the major salivary glands, exclusive of malignant lymphomas.[3] The majority of metastatic primary tumors to the major salivary glands are squamous cell carcinomas and melanomas from the head and neck that presumably reach the parotid gland via the lymphatic system; infraclavicular primary tumors, such as the lung, kidney, and breast, reach the salivary glands by a hematogenous route.[97,98,99] The peak incidence for metastatic tumors in the salivary glands is reported to be in the seventh decade of life.[3]

Stage Information for Salivary Gland Cancer

In general, tumors of the major salivary glands are staged according to size, extraparenchymal extension, lymph node involvement (in parotid tumors, whether or not the facial nerve is involved), and presence of metastases.[1,2,3,4] Tumors arising in the minor salivary glands are staged according to the anatomic site of origin (e.g., oral cavity and sinuses).

Clinical stage, particularly tumor size, may be the critical factor to determine the outcome of salivary gland cancer and may be more important than histologic grade.[5,6] Diagnostic imaging studies may be used in staging. With excellent spatial resolution and superior soft tissue contrast, magnetic resonance imaging (MRI) offers advantages over computed tomographic scanning in the detection and localization of head and neck tumors. Overall, MRI is the preferred modality for evaluation of suspected neoplasms of the salivary glands.[7]

Definitions of TNM

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define salivary gland cancer.[5]

Treatment Option Overview

The minimum therapy for low-grade malignancies of the superficial portion of the parotid gland is a superficial parotidectomy. For all other lesions, a total parotidectomy is often indicated. The facial nerve or its branches should be resected if involved by tumor; repair can be done simultaneously. Growing evidence suggests that postoperative radiation therapy augments surgical resection, particularly for the high-grade neoplasms, when margins are close or involved, when tumors are large, or when histologic evidence of lymph node metastases is present.[1,2,3,4,5,6,7,8] Clinical trials, which have been completed in the United States and England, indicate that fast neutron-beam radiation therapy improves disease-free survival and overall survival in patients with unresectable tumors or for patients with recurrent neoplasms.[9,10,11,12] Facilities with fast neutron-beam radiation therapy are of limited availability in the United States. Accelerated hyperfractionated photon-beam radiation therapy has also resulted in high rates of long-term local regional controls.[13,14] The use of chemotherapy for malignant salivary gland tumors remains under evaluation.[15,16,17,18,19]

Stage I Major Salivary Gland Cancer

Low-grade stage I tumors of the salivary gland are curable with surgery alone.[1,2,3] Radiation therapy may be used for tumors for which resection involves a significant cosmetic or functional deficit or as an adjuvant to surgery when positive margins are present.[4] Neutron-beam therapy is effective in the treatment of poor-prognosis patients with malignant salivary gland tumors.[5,6,7]

High-grade stage I salivary gland tumors that are confined to the gland in which they arise may be cured by surgery alone, though adjuvant radiation therapy may be used, especially with the presence of positive margins.

Low-grade Tumors

Standard treatment options:

Surgery alone.

Postoperative radiation therapy should be considered when the resection margins are positive.

High-grade Tumors

Standard treatment options:

Localized high-grade salivary gland tumors that are confined to the gland in which they arise may be cured by radical surgery alone.

Postoperative radiation therapy may improve local control and increase survival rates for patients with high-grade tumors, positive surgical margins, or perineural invasion.[8][Level of evidence: 3iiiDii][9,10,11]

Treatment options under clinical evaluation:

Clinical trials exploring newer methods of local control are appropriate. The role of chemotherapy remains under evaluation, though data suggest that some salivary gland tumors may be responsive to chemotherapy.[12,13]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I salivary gland cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Stage II Major Salivary Gland Cancer

Low-grade stage II tumors of the salivary gland may be cured with surgery alone.[1,2,3] Radiation therapy as primary treatment may be used for tumors for which resection involves a significant cosmetic or functional deficit or as an adjuvant to surgery when positive margins are present.[4]

High-grade stage II salivary gland tumors that are confined to the gland in which they arise may be cured by surgery alone, though adjuvant radiation therapy may be used, especially if positive margins are present. Primary radiation therapy may be given for tumors that are inoperable, unresectable, or recurrent. Fast neutron-beam radiation therapy has been shown to improve disease-free survival and overall survival in this clinical situation.[5,6,7]

Low-grade Tumors

Standard treatment options:

Surgery alone or with postoperative radiation therapy, if indicated, is appropriate.[8,9]

Chemotherapy should be considered in special circumstances, such as when radiation therapy or surgery is refused.

High-grade Tumors

Standard treatment options:

Localized high-grade salivary gland tumors that are confined to the gland in which they arise may be cured by radical surgery alone.

Postoperative radiation therapy may improve local control and increase survival rates for patients with high-grade tumors, positive surgical margins, or perineural invasion.[10][Level of evidence: 3iiiDii][11,12,13]

Clinical trials exploring ways to improve local control with radiation therapy and/or radiosensitizers are appropriate. The role of chemotherapy is also under study.[15,16]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II salivary gland cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Stage III Major Salivary Gland Cancer

Patients with low-grade stage III tumors of the salivary gland may be cured with surgery alone.[1,2,3] Radiation therapy as primary treatment is not often required but may be used for tumors for which resection involves a significant cosmetic or functional deficit, or as an adjuvant to surgery when positive margins are present.[4] Patients with low-grade tumors that have spread to lymph nodes may be cured with resection of the primary tumor and the involved lymph nodes, with or without radiation therapy. Neutron-beam therapy is effective in the treatment of patients with tumors that have spread to local lymph nodes.

Patients with high-grade stage III salivary gland tumors that are confined to the gland in which they arise may be cured by surgery alone, though adjuvant postoperative radiation therapy may be used, especially if positive margins are present. Primary conventional x-ray radiation therapy may provide palliation for patients with unresectable tumors. Fast neutron beams, however, have been reported to improve disease-free survival and overall survival in this clinical situation.[5,6,7] Patients with tumors that have spread to regional lymph nodes should have a regional lymphadenectomy as part of the initial surgical procedure. Adjuvant radiation therapy for these tumors may reduce the local recurrence rate.

Low-grade Tumors

Standard treatment options:

Surgery alone or with postoperative radiation therapy, if indicated, is appropriate.

Chemotherapy should be considered in special circumstances, such as when radiation or surgery is refused or when tumors are recurrent or nonresponsive.

Treatment options under clinical evaluation:

Data in which fast neutron-beam radiation therapy has been used have indicated superior results when compared with conventional radiation therapy using x-rays. The role of chemotherapy is under evaluation.[5,8,9,10]

High-grade Tumors

Standard treatment options:

Patients with localized high-grade salivary gland tumors that are confined to the gland in which they arise may be cured by radical surgery alone.[11,12]

Postoperative radiation therapy may improve local control and increase survival rates for patients with high-grade tumors, positive surgical margins, or perineural invasion.[13][Level of evidence: 3iiiDii][14,15,16]

Fast neutron-beam radiation therapy or accelerated hyperfractionated photon-beam schedules have been reported to be more effective than conventional x-ray therapy in the treatment of patients with inoperable, unresectable, or recurrent malignant salivary gland tumors.[5,6,7,17]

Treatment options under clinical evaluation:

Clinical trials exploring ways to improve local control with radiation therapy and/or radiosensitizers and with chemotherapy are under evaluation.[8,9,10,18,19]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III salivary gland cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Stage IV Major Salivary Gland Cancer

Standard therapy for patients with tumors that have spread to distant sites is not curative.

Standard treatment options:

Fast neutron-beam radiation therapy or accelerated hyperfractionated photon-beam schedules have been reported to be more effective than conventional x-ray therapy in the treatment of patients with inoperable, unresectable, or recurrent malignant salivary gland tumors.[1,2,3,4,5]

Treatment options under clinical evaluation:

Patients with stage IV salivary gland cancer should be considered candidates for clinical trials. Their cancer may be responsive to aggressive combinations of chemotherapy and radiation. Patients with any metastatic lesions could be considered for clinical trials. Chemotherapy using doxorubicin, cisplatin, cyclophosphamide, and fluorouracil as single agents or in various combinations is associated with modest response rates.[6,7,8,9,10,11,12,13,14]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV salivary gland cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Recurrent Major Salivary Gland Cancer

The prognosis for any treated cancer patient with progressing or relapsing disease is poor, regardless of cell type or stage. Selecting further treatment depends on many factors, including the specific cancer, prior treatment, site of recurrence, and individual patient considerations. Fast neutron-beam radiation therapy is superior to conventional radiation therapy using x-rays and may be curative in selected patients with recurrent disease.[1]

Disease-free survival and overall survival for patients with inoperable, unresectable, or recurrent malignant salivary gland tumors is superior in patients treated with fast neutron-beam radiation therapy as compared to those treated with conventional x-ray radiation therapy.[2,3,4,5] Clinical trials are appropriate and should be considered when possible.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent salivary gland cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Changes to This Summary (11 / 7 / 2014)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of salivary gland cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,

be cited with text, or

replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Salivary Gland Cancer Treatment are:

Scharukh Jalisi, MD, FACS (Boston University Medical Center)

Eva Szabo, MD (National Cancer Institute)

Minh Tam Truong, MD (Boston University Medical Center)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

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